With respect to intraoral administration, the most pertinent prior art reference known to applicants is U.S. Pat. No. 4,229,447 to Porter which discloses a method of administering certain benzodiazepines sublingually and buccally. Porter specifically mentions the sublingual or buccal administration of diazepam, lorazepam, oxazepam, temazepam and chlorodiazepoxide and describes two generic structures of benzodiazepines that may be administered sublingually or buccally.
The compound shown below is contemplated by the generic structures in Porter. All of the benzodiazepines disclosed and the generic structure described in Porter are BZ.sub.1 -BZ.sub.2 receptor non-specific since they lack the trifluoro ethyl group pendant at the N position of the "B" ring which confers BZ.sub.1 specificity. ##STR1##
Porter's method is based on the rapid buccal or sublingual absorption of selected benzodiazepines to attain effective plasma concentration more rapidly than oral administration. In contrast, while parenteral administration provides a rapid rise of blood levels of the benzodiazepines, parenteral administration is frequently accompanied by pain and irritation at the injection site and may require sterilization of the preparatives and the hypodermic syringes.
Porter points out that the intraoral, i.e., buccal or sublingual administration, of lipid soluble benzodiazepines results in therapeutic levels resembling parenteral administration without some of the problems associated with parenteral administration. Porter's administration technique for benzodiazepines in general builds on a long established knowledge in pharmacology that a drug absorbed in the intraoral route gives rise to more rapid absorption than the same drug swallowed into the stomach. What is not recognized by Porter, however, are concerns with first-pass metabolism which can be avoided either with the sublingual or parenteral route of drug administration of certain benzodiazepines.
Porter does not recognize that first-pass metabolism designates the drug intestinal absorption with subsequent entry directly into the portal blood supply leading to the liver and that the liver in turn rapidly absorbs and metabolizes the drug with its first-pass high concentration through the liver. In addition, some first pass metabolism may occur during the absorption process into the intestine. Thus, large amounts of the drug may never be seen by the systemic circulation or drug effect site. Porter further does not recognize that the more rapid metabolism via the first-pass metabolism route can lead to accelerated desalkylation with formation of high plasma concentrations of an unwanted metabolite.
Thus, applicants' concern with avoiding the degradation of the parent compound and its desired positive effect and avoiding the metabolism of the parent compound to an undesired metabolite is neither recognized nor addressed by Porter, who only addresses the ability of the oral mucous membranes to absorb certain benzodiazepines fast and achieve high plasma levels of these benzodiazepines quickly.
The specific drug for which this phenomenon was demonstrated by Porter was lorazepam which has a simple metabolism that results in it not being metabolized to active compounds. Also, and very significantly, the issue of human nervous system receptor specificity and activation for BZ.sub.1 and BZ.sub.2 type receptors is not recognized by Porter either generally or with reference specifically to trifluorobenzodiazepines.
U.S. Pat. No. 3,694,552 to Hester discloses that 3-(5-phenyl-3H-1,4-benzodiazepine-2-yl) carbazic acid alkyl esters, which are useful as sedatives, hypnotics, tranquilizers, muscle relaxants, and anticonvulsants, can be administered sublingually. Subsequently issued U.S. Pat. No. 4,444,781 to Hester specifically teaches that 8-chloro-1-methanol-6-(o-chlorophenyl)-4H-s-triazolo [4,3-a][1,4]-benzodiazepine therapeutic compounds, which are useful as soporifics, can be suitably prepared for sublingual use.
Also, U.S. Pat. No. 4,009,271 to vonBebenburg et al. discloses that 6-aza-3H-1,4-benzodiazepines and 6-aza-1,2-dihydro-3H-1,4-benzodiazepines (which have pharmacodynamic properties including psychosedative and anxiolytic properties as well as antiphlogistic properties) can be administered enterally, parenterally, orally or perlingually.
The chemical formula of nefazodone is 2-(3-(4-(3-chlorophenyl)-1-piperazinyl)propyl-5-ethyl-2,4-dihydro-4-(2-phe noxyethyl)-3H-1,2,4-triazol-3-one hydrochloride and it is abbreviated as NEF.
Patients with obsessive compulsive disorder respond to meta-chlorophenylpiperazine (abbreviated as mCPP), an undesirable metabolite of NEF, by becoming much more anxious and obsessional, as reported by Zohar et al. in "Serotonergic Responsivity in Obsessive Compulsive Disorder: Comparison of Patients and Healthy Controls", Arch. Gen. Psychiatry, Vol. 44, pp. 946-951 (1987). The peak in the anxiousness and obsessional behaviors is observed within 3 hours of mCPP administration and the duration of the worsening ranges from several hours to as much as 48 hours. Much more significantly, mCPP induced a high rate of emergence of entirely new obsessions or the reoccurrence of obsessions that had not been present in the patients for several months. Patients also reported being more depressed and dysphoric.
More specifically, Zohar et al. administered 0.5 mg/kg of mCPP orally to subjects in eliciting their obsessional symptoms. The peak plasma concentration in the control patients was 33.4.+-.17.34 ng/ml, whereas, in the obsessional patients, the peak plasma concentration inducing the obsessional behavior was 26.9 ng/ml.+-.12.33.
Furthermore, Hollander et al., in "Serotonergic Noradrenergic Sensitivity in Obsessive Compulsive Disorder: Behavioral Findings", Am. J. Psychiatry, Vol. 1945, pp. 1015-1017, (1988), have reported many of these obsessional worsening effects in obsessive compulsive patients.
Additionally, Kahn et al., in "Behavioral Indications for Serotonin Receptor Hypersensitivity in Panic Disorder", Psychiatry Res., Vol. 25, pp. 101-104 (1988), have reported mCPP induces anxiety in a group of panic disorder patients.
Moreover, Walsh et al., as reported in "Neuroendocrine and Temperature Effects of Nefazodone in Healthy Volunteers", Biol. Psychiatry, Vol. 33, pp. 115-119 (1933), administered oral doses of 50 mg and 100 mg of NEF to normal subjects and measured NEF and its metabolite mCPP. For the 50 mg dose, the NEF/mCPP area under the curve (abbreviated as AUC) ratio was 1.58. For the 100 mg dose, the AUC ratio was 1.63, indicating that within the first 3 hours, NEF is substantially metabolized to mCPP at levels considerably above the mCPP levels that Zohar et al., supra, found to induce anxiety and obsessional states in susceptible individuals.
In studies in dogs, intravenous dosing of NEF reduced plasma mCPP Cmax by 50% from that found with oral dosing, as reported by Shukla et al., in "Pharmacokinetics, Absolute Bioavailability, and Disposition of [.sup.14 C] Nefazodone in the Dog", Drug Metab. Disposition, Vol. 21, No. 3, pp. 502-507 (1993).
Also, a discussion of bupropion and its three major metabolites, erythrohydrobupropion, hydroxybupropion, and threohydrobupropion, as well as the strong relationship of higher hydroxybupropion metabolite concentrations in therapeutically non-responding patients in contrast to responders, can be seen in Posner et al., "The Disposition of Bupropion and Its Metabolites in Healthy Male Volunteers after Single and Multiple Doses", Vol. 29, Eur. J. Clin. Pharmacol., pp. 97-103 (1985) and Bolden et al., "Bupropion in Depression", Vol. 45, Arch. Gen. Psychiatry, pp. 145-149 (February 1988). Hydroxybupropion, therefore, represents an unwanted metabolite.
Background information with respect to skin administration of drugs is as follows.
In one embodiment of the present invention, use of skin (i.e., transdermal) administration as a primary vehicle for administration of drugs to bypass the GI tract absorption and portal vein entry into the liver is contemplated.
Highly lipid soluble substances are absorbed through the skin and even are the basis for the toxicity for such lipid soluble drugs as the insecticides and organic solvents. Absorption through the skin can be enhanced by suspending the drug in an oily vehicle and rubbing it onto the skin, a method known as inunction.
A variety of improvements in transdermal administration of drugs has transpired over the last few years.
For example, ultrasound mediated transdermal delivery, in which low frequency ultrasound application increases the permeability of the skin to many drugs including higher molecular weight drugs, was recently described by Mitragotri, Blankschtein, and Langer in "Ultrasound-Mediated Transdermal Protein Delivery", Science, 269:850-853 (1995).
In addition, when ionizable drugs such as dexamethasone sodium phosphate or lidocane hydrochloride are used, the electro-transport system of iontophoresis can be used to drive the drugs through the skin such as in the use of the PHORESOR.RTM. made by IOMED. Also, Alza Corporation has also been active in developing electro-transport systems for drug delivery. (See, Alza U.S. Pat. D384,745 issued Oct. 7, 1997; D372,098 issued Jul. 23, 1996; U.S. Pat. No. 5,629,019 issued May. 13, 1997; and Ser. No. 566,817 issued Sep. 16, 1997. The disclosures of these patents are incorporated herein by reference.)
The advantages of skin administration to the systemic circulation include:
1) bypassing the gastrointestinal portal vein entry into the liver and its first-pass metabolism,
2) sustained blood levels without multiday dosing, and
3) blood concentrations of drug controllable within and between patients in a narrow range
See, Shaw, J. E. and Chandrasekaran, S. K., "Skin as a Mode for Systemic Drug Administration", Greaves, M. W. and Shuster, S. (eds), Pharmacology of the Skin II, Springer-Verlag:New York, pp. 115-122 (1989).
Background information with respect to skin patches, a preferred embodiment, is described as follows.
For instance, administration of nicotine by way of a skin patch can be seen in U.S. Pat. No. 4,920,989 to Rose, Jarvik, and Rose, and in U.S. Pat. No. 5,016,652 to Rose and Jarvik.
Of the rapid development of techniques for administering drugs by skin patches, one improvement is the development by Fuisz Technology LTD of a melt spinable carrier agent such as sugar which is combined with a medicament and then converted to a fiber for by melt-spinning. (See, U.S. Pat. No. 4,855,362, entitled "Rapidly Dissolvable Medicinal Dosage Unit and Method of Manufacture".) This facilitates dissolving the medication onto any surface area when wetted such as with skin moisture. It is also readily applicable to sublingual or buccal administration.
These skin delivery systems are well known to those practiced in the art of clinical pharmacology. The disclosures of these patents regarding skin patches are incorporated herein by reference. (See also, Southam, M. A., "Transdermal Fentanyl Therapy: System Design, Pharmacokinetics and Efficacy", Anti-Cancer Drugs, 6 Suppl. 3:29-34, (1995) as an example of skin patches.)
Background information with respect to inhalation of drugs is as follows.
Inhalation techniques for administering drugs have been known for centuries. Witness the use of smoking to administer opiates and nicotine.
Also, inhalation of gases is a classical means of inducing surgical anesthesia and as well volatile drugs may be inhaled in this manner.
In another embodiment of the present invention, the focus is on inhalation administration of medicaments, particularly via inhalators, such as for dry powders or aerosols. As with skin drug administration, inhalation drug administration provides a means of bypassing the gastrointestinal portal vein entry first-pass metabolism and as well provides a means of rapid access to the general circulation. See, Benet, L. Z., Kroetz, D. L. and Sheiner, L. B., "Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination", Hardman, L. G. et al. (eds), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9.sup.th Ed, McGraw-Hill:New York, pp. 3-27, (1996).
Drugs delivered from inhalators are airborne fine particles. The particles may be aerosolized suspensions (admixed with a propellant gas, i.e., a chlorofluorocarbon) or may be dispersed powders (generally admixed with an excipient). These particles may be either liquids or solids and are defined by the mass median aerodynamic diameter (MMAD). Thus, solid particulate(s) and liquid droplet(s) with the same unit density have the same average rate of settling (e.g., in the lungs).
The size of the airborne particles is important. If they are larger than 10 micrometers diameter, they are unlikely to reach the lungs for deposit. If they are smaller than 0.5 micrometers diameter, they may be exhaled again.
One of the problems with inhalation delivery is that only approximately 10-20% of the drug is delivered to the lung alveoli. The rest is deposited into the oro-pharynx. If this were swallowed, it would go into a gastrointestinal absorption portal vein liver entry and metabolism pathway. Thus, mouth rinsing is frequently recommended.
In the present invention, this deposition into the oropharynx does not present the same type of problem. Since the airborne drug being inhaled is in a fine particle form with the appropriate formulation, it will be rapidly absorbed in the oral cavity if swallowing is delayed as it will with sublingual administration. Thus, inhalation administration presents a combined buccalingual pathway (as well as an oropharyngeal pathway) plus the lung absorption means of bypassing the gastrointestinal liver first-pass metabolism.
There are several inhalator delivery systems contemplated as useful in the present invention.
One is a traditional nebulizer which works via a mechanism similar to the familiar perfume atomizer. The airborne particles are generated by a jet of air from either a compressor or compressed gas cylinder passing through the device. In addition, newer forms utilize an ultrasonic nebulizer by vibrating the liquid at speeds of up to about 1 MHZ.
Another type of inhalator delivery system is the metered dose inhaler (MDI). This has been widely used because of its convenience and usually contains a suspension of the drug in a aerosol propellant. However, the MDI has fallen into disfavor recently due to problems with chlorofluorocarbon propellants causing depletion of the earth's ozone layer, which has led to increased use of still another type of inhalator delivery system, namely the dry powder inhaler.
The typical dry powder inhaler has the appropriate dose often placed in a capsule along with a flow aid or filler excipient, such as large lactose or glucose particles. Inside the device, the capsule is initially either pierced by needles (SPINHALER.RTM.) or sheered in half (ROTOHALER.RTM.). Propellers turning cause the capsule contents to enter the air stream and to be broken up into small particles. (See also, DISKHALER.RTM., TURBUHALER.RTM., plus numerous other dry powder inhalation delivery devices.) For a review, see Taburet, A. M. and Schmit, B., "Pharmacokinetic Optimisation of Asthma Treatment", Clin. Pharmacokinet., 26(5):396-418 (1994).
More recently, Inhale Therapeutic Systems has created an inhalator delivery system that integrates customized formulation and proprietary fine powder processing and packaging technologies with their proprietary inhalation device for efficient reproducible deep-lung delivery. Their process of providing agglomerate composition compounds of units of aggregated fine particles and methods for manufacture and use of the units has recently been covered by a series of patents. The particle size containing the drug is in the optimum range for deep-lung delivery and has a suitable friability range. The U.S. patents covering these methods include U.S. Pat. No. 5,458,135 issued Oct. 17, 1996, U.S. Pat. No. 5,607,915 issued Mar. 4, 1997 and U.S. Pat. No. 5,654,007 issued Aug. 5, 1997. (See also, U.S. Pat. No. 5,655,516 issued Aug. 12, 1997.) The disclosures of these patents are incorporated herein by reference.
Other potential improvements of pulmonary inhalation of drugs via an inhalator delivery system include the use of liposomes (microscopic phospholipid vesicles). The liposomal delivery of drugs slows the uptake of drug absorption from the lungs thus, providing a sustained drug release. (See, Hung, O. R., Whynot, S. C., Varvel, J. R., Shafer, S. L. and Mezel, M., "Pharmacokinetics of Inhaled Liposome-Encapsulated Fentanyl", Anesthesiol., 82:277-284 (1995).
The key factor to be considered here is that most inhalation delivery devices are currently used for treatment of lung conditions in which it is important to supply the active drug to a site in the lungs where the drug acts for a period of time before being absorbed into the general circulation. Since the lungs have a surface area of at least the size of a tennis court and a series of thin cell sacks (alveoli) that are highly vascularized, the lungs provide a large surface area for absorption of drugs. However, in the present invention, the inhalation technique provides a means of not only administering drugs to the lungs, but also, because of the small particle size, a means of delivering highly absorbable small particles to multiple sites in the oropharyngeal pathway. Thus, the drug is dispersed to a topographically much larger mucosal absorption area than would occur from sublingual and/or buccal administration, and additionally, provided is the 10-20% absorption by lung administration.
Moreover, general background information with respect to dry powder inhalers can be seen in U.S. Pat. No. 2,642,063 to Brown; U.S. Pat. No. 3,807,400 to Cocozza; U.S. Pat. No. 3,906,950 to Cocozza; U.S. Pat. No. 3,991,761 to Cocozza; U.S. Pat. No. 3,992,144 to Jackson; U.S. Pat. No. 4,013,075 to Cocozza; U.S. Pat. No. 4,371,101 to Cane and Farneti; U.S. Pat. No. 4,601,897 to Saxton; U.S. Pat. No. 4,841,964 to Hurka and Hatschek; U.S. Pat. No. 4,955,945 to Weick; U.S. Pat. No. 5,173,298 to Meadows; U.S. Pat. No. 5,369,117 to Sallmann, Gschwind, and Francotte; U.S. Pat. No. 5,388,572 to Mulhauser, Karg, Foxen, and Brooks; U.S. Pat. No. 5,388,573 to Mulhauser and Karg; U.S. Pat. No. 5,394,869 to Covarrubias; U.S. Pat. No. 5,415,162 to Casper, Taylor, Leith, Leith, and Boundy; U.S. Pat. No. 5,503,869 to Van Oort; International Publication No. WO 92/00115 to Gupte, Hochrainer, Wittekind, Zierenberg, and Knecht; International Publication No. WO 94/20164 to Mulhauser and Karg; and International Publication No. WO 93/24166 to Wright, Seeney, Hughes, Revell, Paton, Cox, Rand, and Pritchard. The disclosures of all of these background patents vis-a-vis drug inhalers are incorporated herein by reference.